Cell 166, 624–636 (2016)

Responses to bacterial infections are initiated by pattern recognition receptors (PRRs) of the innate immune system that detect pathogenassociated molecular patterns (PAMPs), molecules produced by degradation of the invading microbe. For example, recent work has shown that degradation of Staphylococcus aureus peptidoglycan (PGN) in macrophages promotes assembly of NOD-like receptor family pyrin domain–containing 3 (NLRP3) inflammasomes that induce secretion of cytokines such as IL-1b. Wolf et al. now identify the molecular players in this pathway, showing that N-acetylglucosamine (NAG) acts as the PAMP and hexokinase as its PRR. The authors tested possible PGN degradation products and found that cytoplasmic NAG, but not glucosamine (its deacetylated form), led to NLRP3 activation and IL-1b secretion. Because PGN-induced inflammation is thought to involve mitochondria, a search for candidate NAG targets led the authors to hexokinase, a glycolytic enzyme that is localized to the mitochondrial outer membrane and inhibited by NAG. NAG treatment led to hexokinase release into the cytoplasm, which was necessary and sufficient for NLRP3 inflammasome formation. Furthermore, treatment of cells with known hexokinase inhibitors or metabolic intermediates that back up the glycolytic pathway also stimulated hexokinase release and inflammasome formation, uncovering a previously unknown link between central metabolism and inflammatory pathways that may have implications in certain metabolic diseases.